Fluoro and sulphonylamino containing 3,6-disubstituted azabicyclo (3.1.0) hexane derivatives as muscarinic receptor antagonists

ABSTRACT

This invention generally relates to the derivatives of novel 3,6 disubstituted azabicyclo[3.1.0] hexane&#39;s. The compounds of this invention are MUSCARINIC receptor antagonists which are useful, inter-ail for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through MUSCARINIC receptors. The invention also relates to processes for the preparation of the compounds of the invention, pharmaceutical compositions containing the compounds of the present invention and the methods of treating the diseases mediated through MUSCARINIC receptors.

FIELD OF THE INVENTION

This invention generally relates to the derivatives of novel 3,6disubstituted azabicyclo[3.1.0]hexanes.

The compounds of this invention are muscarinic receptor antagonistswhich are useful, inter-alia for the treatment of various diseases ofthe respiratory, urinary and gastrointestinal systems mediated throughmuscarinic receptors.

The invention also relates to processes for the preparation of thecompounds of the invention, pharmaceutical compositions containing thecompounds of the present invention and the methods of treating thediseases mediated through muscarinic receptors.

BACKGROUND OF THE INVENTION

Muscarinic receptors as members of the G Protein Coupled Receptors(GPCRs) are composed of a family of 5 receptor sub-types (M₁, M₂, M₃, M₄and M₅) and are activated by the neurotransmitter acetylcholine. Thesereceptors are widely distributed on multiple organs and tissues and arecritical to the maintenance of central and peripheral cholinergicneurotransmission. The regional distribution of these receptor sub-typesin the brain and other organs has been documented. For example, the M₁subtype is located primarily in neuronal tissues such as cereberalcortex and autonomic ganglia, the M₂ subtype is present mainly in theheart where it mediates cholinergically induced bradycardia, and the M₃subtype is located predominantly on smooth muscle and salivary glands(Nature, 1986; 323: 411; Science, 1987; 237: 527).

A review in Current opinions in Chemical Biology, 1999; 3: 426, as wellas in Trends in Pharmacological Sciences, 2001; 22: 409 by Eglen et.al., describe the biological potentials of modulating muscarinicreceptor subtypes by ligands in different disease conditions likeAlzheimer's disease, pain, urinary disease condition, chronicobstructive pulmonary disease etc.

A review in J. Med. Chem., 2000; 43: 4333 by Christian C. Felder et. al.describes therapeutic opportunities for muscarinic receptors in thecentral nervous system and elaborates on muscarinic receptor structureand function, pharmacology and their therapeutic uses.

The pharmacological and medical aspects of the muscarinic class ofacetylcholine agonists and antagonists are presented in a review inMolecules, 2001, 6: 142.

N. J. M. Birdsall et. al. in Trends in Pharmacological Sciences, 2001;22: 215 have also summarized the recent developments on the role ofdifferent muscarinic receptor subtypes using different muscaranicreceptor of knock out mice.

Muscarinic agonists such as muscarine and pilocarpine and antagonists issuch as atropine have been known for over a century, but little progresshas been made in the discovery of receptor subtype-selective compoundsmaking it difficult to assign specific functions to the individualreceptors. Although classical muscarinic antagonists such as atropineare potent bronchodilators, their clinical utility is limited due tohigh incidence of both peripheral and central adverse effects such astachycardia, blurred vision, dryness of mouth, constipation, dementia,etc. Subsequent development of the quarterly derivatives of atropinesuch as ipratropium bromide are better tolerated than parenterallyadministered options but most of them are not ideal anti-cholinergicbronchodilators due to lack of selectivity for muscarinic receptorsub-types. The existing compounds offer limited therapeutic benefit dueto their lack of selectivity resulting in dose limiting side-effectssuch as thirst, nausea, mydriasis and those associated with the heartsuch as tachycardia mediated by the M₂ receptor.

Annual review of Pharmacological Toxicol., 2001; 41: 691, describes thepharmacology of the lower urinary tract infections. Although antimuscarinic agents such as oxybutynin and tolterodine that actnon-selectively on muscarinic receptors have been used for many years totreat bladder hyperactivity, the clinical effectiveness of these agentshas been limited due to the side effects such as dry mouth, blurredvision and constipation. Tolterodine is considered to be generallybetter tolerated than oxybutynin. (W. D. Steers et. al. in Curr. Opin.Invest. Drugs, 2: 268, C. R. Chapple et. al. in Urology, 55: 33), SteersWD, Barrot DM, Wein AJ, 1996, Voiding dysfunction: diagnosisclassification and management. In Adult and Pediatric Urology, ed. JYGillenwatter, JT Grayhack, SS Howards, JW Duckett, pp 1220-1325, St.Louis, Mo.; Mosby. 3^(rd) edition.)

Despite these advances, there remains a need for development of newhighly selective muscarinic antagonists which can interact with distinctsubtypes, thus avoiding the occurrence of adverse effects.

Compounds having antagonistic activity against muscarinic receptors havebeen described in Japanese patent application Laid Open Number92921/1994 and 135958/1994; WO 93/16048; U.S. Pat. No. 3,176,019; GB940,540; EP 0325 571; WO 98/29402; EP 0801067; EP 0388054; WO 9109013;U.S. Pat. No. 5,281,601. U.S. Pat. Nos. 6,174,900, 6,130,232 and5,948,792; WO 97/45414 are related to 1,4-disubstituted piperidinederivatives; WO 98/05641 describes fluorinated, 1,4-disubstituedpiperidine derivatives; WO 93/16018 and WO96/33973 are other close artreferences.

A report in J. Med. Chem., 2002; 44:984, describes cyclohexylmethylpiperidinyl triphenylpropioamide derivatives as selective M₃ antagonistdiscriminating against the other receptor subtypes.

SUMMARY OF THE INVENTION

The present invention provides novel fluoro and sulphonylaminocontaining 3,6-disubstituted azabicyclo[3.1.0]hexanes as muscarinicreceptor antagonists which are useful as safe and effective therapeuticor prophylactic agents for the treatment of various diseases of therespiratory, urinary and gastrointestinal systems and process for thesynthesis of the novel compounds. Substitution on the cycloalkyl moeityimproves both metabolic stability as well as subtype selectivity.

The invention also provides pharmaceutical compositions containing thenovel compounds together with acceptable carriers, excipients ordiluents which are useful for the treatment of various diseases of therespiratory, urinary and gastrointestinal systems.

The present invention also includes within its scope prodrugs of thenovel compounds. In general, such prodrugs will be functionalizedderivatives of these compounds which readily get converted in vivo intothe defined compounds. Conventional procedures for the selection andpreparation of suitable prodrugs are known to the artisan skilled in theart.

The invention also includes the enantiomers, diastereomers, N-oxides,polymorphs, pharmaceutically acceptable salts and pharmaceuticallyacceptable solvates of these compounds as well as metabolites having thesame type of activity.

The invention further includes pharmaceutical compositions comprisingthe compounds of the present invention, their prodrugs, metabolites,enantiomers, diastereomers, N-oxides, polymorphs, solvates orpharmaceutically acceptable salts thereof, in combination with apharmaceutically acceptable carrier and optionally included excipients.

Other advantages of the invention will be set forth in the descriptionwhich follows, and in part will be apparent from the description or maybe learnt by the practice of the invention. The objects and theadvantages of the invention may be realized and obtained by means of themechanisms and combinations pointed out in the appended claims.

In accordance with one aspect of the present invention, there isprovided a compound having the structure of Formula I:

and its pharmaceutically acceptable salts, pharmaceutically acceptablesolvates, esters, enantiomers, diastereomers, N-oxides, polymorphs,prodrugs, metabolites, wherein

-   Ar represents an aryl or a heteroaryl ring having 1-2 hetero atoms    selected from the group consisting of oxygen, sulphur and nitrogen    atoms, the aryl or heteroaryl rings may be unsubstituted or    substituted by one to three substituents independently selected from    lower alkyl (C₁-C₄), lower perhalo alkyl (C₁-C₄), cyano, hydroxy,    nitro, lower alkoxy (C₁-C₄), lower perhalo alkoxy (C₁-C₄),    unsubstituted amino, N-lower alkyl (C₁-C₄) amino or N-lower alkyl    (C₁-C₄) amino carbonyl;-   R₁ represents a hydrogen, hydroxy, hydroxymethyl, amino, alkoxy,    carbamoyl or halogen (e.g. fluorine, chlorine, bromine and iodine);-   R₂ represents C₃-C₇ cycloalkyl ring in which from 1 to 4 hydrogen    atoms are substituted with fluorine atoms, or sulphonamide    derivatives;-   W represents (CH₂)_(p), where p represents 0 to 1;-   X represents an oxygen, sulphur, nitrogen or no atom;-   Y represents CHR₅CO wherein R₅ represents hydrogen or methyl or    (CH₂)_(q) wherein q represents 0 to 4;-   Z represents oxygen, sulphur or NR₁₀, wherein R₁₀ represents    hydrogen, C₁₋₆ alkyl;-   Q represents (CH₂)_(n) wherein n represents 1 to 4, or CHR₈ wherein    R₈ represents H. OH, C₁₋₆, alkyl, alkenyl, alkoxy or CH₂CHR₉,    wherein R₉ represents H, OH, lower alkyl (C₁-C₄) or lower alkoxy    (C₁-C₄);-   R₆ and R₇ are independently selected from H, CH₃, COOH, CONH₂, NH₂,    CH₂NH₂; and-   R₄ represents a C₁-C₁₅ saturated or unsaturated aliphatic    hydrocarbon group in which from 1 to 6 hydrogen atoms may be    substituted with the group independently selected from halogen,    arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl having    1 to 2 hetero atoms selected from the group consisting of nitrogen,    oxygen and sulphur atoms with an option that any 1 to 3 hydrogen    atoms on the ring in said arylalkyl, arylalkenyl, hetero arylalkenyl    group may be substituted with lower alkyl (C₁-C₄), lower perhalo    alkyl (C₁-C₄), cyano, hydroxyl, nitro, lower alkoxycarbonyl,    halogen, lower alkoxy (C₁-C₄), lower perhaloalkoxy (C₁-C₄),    unsubstituted amino, N-lower alkylamino (C₁-C₄), N-lower alkylamino    carbonyl (C₁-C₄).

In accordance with a second aspect of the present invention, there isprovided a compound having the structure of Formula II (Formula I, whenR₆ and R₇=H) and its pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, esters, enantiomers, diastereomers, N-oxides,polymorphs, prodrugs, metabolites, wherein Ar, R₁, R₂, W, X, Y, Z, Q,and R₄ are as defined for Formula I.

In accordance with a third aspect of the present invention there isprovided a compound having the structure of Formula III (Formula Iwherein W is (CH₂)_(p) where p=0, X is no atom and Y is (CH₂)_(q) whereq=0, R₆=H, R₇=H) and its pharmaceutically acceptable salts,pharmaceutically acceptable solvates, esters, enantiomers,diastereomers, N-oxides, polymorphs, prodrugs, metabolites, wherein Ar,R₁, R₂, Z, Q and R₄ are as defined for Formula I.

In accordance with a fourth aspect of the present invention, there isprovided a compound having the structure of Formula IV [Formula I when Wis (CH₂)_(p) where p=0, X is no atom and Y is (CH₂)_(q) where q=0, R₆=H,R₇=H, R₂=

where R₁₁ is hydrogen or fluoro, R₁₂ is fluoro or sulphonamidederivatives and s represents 1 to 2, R₁ is hydroxy, Ar is phenyl], andits pharmaceutically acceptable salts, pharmaceutically acceptablesolvates, esters, enantiomers, diastereomers, N-oxides, polymorphs,prodrugs, metabolites, wherein R₄, Z and Q are the same as defined forFormula I.

In accordance with a fifth aspect of the present invention, there isprovided a method for treatment or prophylaxis of an animal or humansuffering from a disease or disorder of the respiratory, urinary andgastrointestinal systems, wherein the disease or disorder is mediatedthrough muscarinic receptors.

In accordance with a sixth aspect of the present invention, there isprovided a method for treatment or prophylaxis of an animal or humansuffering from a disease or disorder associated with muscarinicreceptors, comprising administering to a patient in need thereof, aneffective amount of muscarinic receptor antagonist compound as describedabove.

In accordance with a seventh aspect of the present invention, there isprovided a method for treatment or prophylaxis of an animal or humansuffering from a disease or disorder of the urinary system which inducesuch urinary disorders as urinary incontinence, lower urinary tractsymptoms (LUTS), etc.; respiratory system disorders such as bronchialasthma, chronic obstructive pulmonary disorders (COPD), pulmonaryfibrosis, etc.; and gastrointestinal system disorders such as irritablebowel syndrome, obesity, diabetes and gastrointestinal hyperkinesis withcompounds as described above, wherein the disease or disorder isassociated with muscarinic receptors.

In accordance with the eighth aspect of the present invention, there areprovided processes for preparing the compounds as described above.

The compounds of the present invention are novel and exhibit significantpotency in terms of their activity, which was determined by in vitroreceptor binding and functional assays and in vivo experiments usinganaesthetized rabbit. The compounds that were found active in in vitroassay were tested in vivo. Some of the compounds of the presentinvention were found to be potent muscarinic receptor antagonists withhigh affinity towards M₃ receptors. Therefore, the present inventionprovides the pharmaceutical compositions for the possible treatment forthe disease or disorders associated with muscarinic receptors. Inaddition, the compounds of the present invention can be administeredorally or parenterally.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention may be prepared by techniqueswell known in the art and familiar to the average synthetic organicchemist. In addition, the compounds of the present invention may beprepared by the following novel and inventive reaction sequences:

The compounds of Formula I of the present invention may be prepared bythe reaction sequence as shown in Scheme I. The preparation comprisescondensing a compound of Formula V with the compound of Formula VIwherein

-   Ar represents an aryl or a heteroaryl ring having 1-2 hetero atoms    selected from the group consisting of oxygen, sulphur and nitrogen    atoms, the aryl or heteroaryl rings may be unsubstituted or    substituted by one to three substituents independently selected from    lower alkyl (C₁-C₄), lower perhalo alkyl (C₁-C₄), cyano, hydroxy,    nitro, lower alkoxy (C₁-C₄), lower perhalo alkoxy (C₁-C₄),    unsubstituted amino, N-lower alkyl (C₁-C₄) amino or N-lower alkyl    (C₁-C₄) amino carbonyl;-   R₁ represents a hydrogen, hydroxy, hydroxymethyl, amino, alkoxy,    carbamoyl or halogen (e.g. fluorine, chlorine, bromine and iodine);-   R₂ represents a C₃-C₇ cycloalkyl ring in which from 1 to 4 hydrogen    atoms are substituted with fluorine atoms, or sulphonamide    derivatives;-   W represents (CH₂)_(p), where p represents 0 to 1;-   x represents an oxygen, sulphur, nitrogen or no atom;-   Y represents CHR₅CO wherein R₅ represents hydrogen or methyl or    (CH₂)_(q) wherein q represents 0 to 4;-   z represents oxygen, sulphur or NR₁₀, wherein R₁₀ represents    hydrogen, C₁₋₆ alkyl;-   Q represents (CH₂)_(n) wherein n represents 1 to 4, or CHR₈ wherein    R₈ represents H, OH, C₁₋₆, alkyl, alkenyl, alkoxy or CH₂CHR₉,    wherein R₉ represents H, OH, lower alkyl (C₁-C₄) or lower alkoxy    (C₁-C₄);-   R₆ and R₇ are independently selected from H, CH₃, COOH, CONH₂, NH₂,    CH₂NH₂; and

P is any protecting group for an amino group, in the presence of acondensing agent to give a protected compound of Formula VII which ondeprotection in the presence of a deprotecting agent in an organicsolvent gives an unprotected intermediate of Formula VIII which isfinally N-alkylated or benzylated with a suitable alkylating orbenzylating agent, L-R₄ to give a compound of Formula I wherein L is anyleaving group and R₄ represents C₁-C₁₅ saturated or unsaturatedaliphatic hydrocarbon groups in which any 1 to 6 hydrogen atoms may besubstituted with the group independently selected from halogen,arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to2 hetero atoms selected from the group consisting of nitrogen, oxygenand sulphur atoms with an option that any 1 to 3 hydrogen atoms on thering in said arylalkyl, arylalkenyl, hetero arylalkenyl group may besubstituted with lower alkyl (C₁-C₄), lower perhalo alkyl (C₁-C₄),cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy(C₁-C₄), lower perhaloalkoxy (C₁-C₄), unsubstituted amino, N-loweralkylamino (C₁-C₄), N-lower alkylamino carbonyl (C₁-C₄).

P is any protecting group for an amino group for a compound of Formula Vand is selected from benzyl and t-butyloxy carbonyl groups.

The reaction of the compound of Formula V with a compound of Formula VIto give a compound of Formula VII is carried out in the presence of acondensing agent which is selected from the group consisting of1-(3-dimethylamino propyl)-3-ethyl carbodiimide hydrochloride (EDC) and1,8-diazabicyclo [5.4.0]undec-7-ene (DBU).

The reaction of the compound of Formula V with a compound of Formula VIto give a compound of Formula VII is carried out in a suitable solventselected from the group consisting of N,N-dimethylformamide,dimethylsulfoxide, toluene, and xylene at a temperature ranging fromabout 0-140° C.

The deprotection of the compound of Formula VII to give a compound ofFormula VIII is carried out with a deprotecting agent which is selectedfrom the group consisting of palladium on carbon, trifluoroacetic acid(TFA) and hydrochloric acid.

The deprotection of the compound of Formula VII to give a compound ofFormula VIII is carried out in a suitable organic solvent selected fromthe group consisting of methanol, ethanol, tetrahydrofuran andacetonitrile at temperatures ranging from about 10-50° C.

The N-alkylation or benzylation of the compound of Formula VIII to givea compound of Formula I is carried out with a suitable alkylating orbenzylating agent, L-R₄ wherein L is any leaving group known in the art,preferably selected from halogen, O-mestyl and O-tosyl group.

The N-alkylation or benzylation of the compound of Formula VIII to givea compound of Formula I is carried out in a suitable organic solventsuch as N,N-dimethylformamide dimethylsulfoxide, tetrahydrofuran andacetonitriie, at temperatures ranging from about 25-100° C.

Suitable salts of the compounds represented by the Formula I wereprepared so as to solubilize the compound in aqueous medium forbiological evaluations. Examples of such salts include pharmacologicallyacceptable salts such as inorganic acid salts (e.g. hydrochloride,hydrobromide, sulphate, nitrate and phosphorate), organic acid salts(e.g. acetate, tartrate, citrate, fumarate, maleate, toluenesulphonateand methanesulphonate). When carboxyl group is included in the Formula Ias a substituent, it may be an alkali metal salt (e.g. sodium,potassium, calcium, magnesium, and the like). These salts may beprepared by the usual prior art techniques, such as treating thecompound with an equivalent amount of inorganic or organic, acid or basein a suitable solvent.

The compound of Formula IV [Formula I, when W is (CH₂)_(p) where p=0, Xis no atom, Y is (CH₂)_(p) where q=O, R₆=H, R₇=H, R₂=

where R₁₁=H or F, R₁₂=F and s represents 1 to 2,R₁=OH, Ar=phenyl] may be prepared by the following reaction sequence asdepicted in Scheme-II

The preparation comprises condensing a compound of Formula IX with thecompound of Formula X wherein Z, Q and s have the same meanings asdefined earlier for Formula I, R₁₁ is hydrogen or fluoro and R₁₂ isfluoro. P is any protecting group for an amino group, in the presence ofa condensing agent to give a protected compound of Formula XI which ondeprotection in the presence of a deprotecting agent in an organicsolvent gives an unprotected intermediate of Formula XIII which isfinally N-alkylated or benzylated with a suitable alkylating orbenzylating agent L-R₄ to give a compound of Formula IV wherein L is anyleaving group and R₄ is defined above.

P is any protecting group for an amino group for a compound of Formula Xand is selected from benzyl and t-butyloxy carbonyl groups.

The reaction of the compound of Formula IX with a compound of Formula Xto give a compound of Formula XI is carried out in the presence of acondensing agent which is selected from the group consisting of1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC) and1,8-diazabicyclo [5.4.0]undec-7-ene (DBU).

The reaction of the compound of Formula IX with a compound of Formula Xto give a compound of Formula XI is carried out in a suitable solventselected from the group consisting of N,N-dimethylformamide,dimethylsulphoxide, toluene, and xylene at a temperature ranging fromabout 0-140° C.

The deprotection of the compound of Formula XI to give a compound ofFormula XII is carried out in a suitable organic solvent selected fromthe group consisting of methanol, ethanol, tetrahydrofuran andacetonitrile at temperatures ranging from about 10-50° C.

The deprotection of the compound of Formula XI to give a compound ofFormula XII is carried out with a deprotecting agent which is selectedfrom the group consisting of palladium on carbon, trifluoroacetic acid(TFA) and hydrochloric acid.

The N-alkylation or benzylation of the compound of Formula XII to give acompound of Formula IV is carried out with a suitable alkylating orbenzylating agent, L-R₄ wherein L is any leaving group known in the art,preferably selected from halogen, O-mestyl and O-tosyl group.

The N-alkylation or benzylation of the compound of Formula XII to give acompound of Formula IV is carried out in a suitable organic solvent suchas N,N-dimethylformamide, dimethylsulphoxide, tetrahydrofuran andacetonitrile, at temperatures ranging from about 10-100° C.

Suitable salts of the compounds represented by the Formula IV wereprepared so as to solubilize the compound in aqueous medium forbiological evaluations. Examples of such salts include pharmacologicallyacceptable salts such as inorganic acid salts (e.g. hydrochloride,hydrobromide, sulphate, nitrate and phosphorate), organic acid salts(e.g. acetate, tartrate, citrate, fumarate, maleate, toluenesulphonateand methanesulphonate). When carboxyl group is included in the Formula Ias a substituent, it may be an alkali metal salt (e.g. sodium,potassium, calcium, magnesium, and the like). These salts may beprepared by the usual prior art techniques, such as treating thecompound with an equivalent amount of inorganic or organic, acid or basein a suitable solvent.

Acid of Formula IX can be synthesized following the procedures describedin J. Org. Chem., 2001; 66:6775; Bioorg. and Med. Chem. 2000; 8:825 andreferences cited therein.

The compound of Formula IV [Formula I, when W is (CH₂)_(p) where p=0, Xis no atom, Y is (CH₂)_(p) where q=O, R₆=R₇=H, R₂=

where R₁₁=H or F, R₁₂=F or sulphonamide and s represents 1 to 2, R₁=OH,Ar=phenyl) can also be prepared by reaction sequence as shown inScheme-III.

The preparation comprises condensing a compound of Formula IX with acompound of Formula XIII wherein Z, Q and R₄ have the same meanings asdescribed earlier for Formula I.

The reaction of the compound of Formula IX with a compound of FormulaXIII is carried out in the presence of a condensing agent which isselected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 1,8-diazabicyclo [5.4.0]undec-7-ene(DBU).

The reaction of the compound of Formula IX with a compound of FormulaXIII is carried out in a suitable solvent selected from the groupconsisting of N,N-dimethylformamide, dimethyl sulfoxide, toluene, andxylene at a temperature ranging from about 0-140° C.

The compound of Formula IV (Formula I, when W is (CH₂)_(p) where p=0, Xis no atom, Y is (CH₂)_(p) where q=0, R₆=R₇=H, R₂=

where R₁₁=H, R₁₂=substituted sulphonamide and s represents 1 to 2,R₁=OH, Ar=phenyl) of the present invention may be prepared by thereaction sequence as shown in Scheme-IV. The preparation comprisescondensing a compound of Formula XIV with a compound of Formula X, whereZ and Q have the same meanings as described earlier for Formula I togive a compound of Formula XV. The starting compound of Formula XIV wasprepared by the known procedure described in Bioorganic and MedicinalChemistry, 2000; 8:825.

The compound of Formula XVI is obtained by the deprotection of FormulaXV in an organic solvent in the presence of a deprotecting agent. Theintermediate of Formula XVI is finally N-alkylated or benzylated withsuitable alkylating or benzylating agent L-R₄ to give a compound ofFormula XVII wherein L is any leaving group and R₄ is the same asdefined above.

P is any protecting group for an amino group for a compound of Formula Xand is selected from benzyl and t-butyloxy carbonyl groups.

The reaction of the compound of Formula XIV with a compound of Formula Xto give a compound of Formula XV is carried out in the presence of acondensing agent which is selected from the group consisting of1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

The reaction of the compound of Formula XIV with a compound of Formula Xto give a compound of Formula XV is carried out in a suitable solventselected from the group consisting of N,N-dimethylformamide,dimethylsulphoxide, toluene, and xylene at a temperature ranging fromabout 0°-140° C.

The deprotection of the compound of Formula XV to give a compound ofFormula XVI is carried out in a suitable solvent selected from the groupconsisting of methanol, ethanol, tetrahydrofuran and acetonitrile attemperature ranging from about 10°-50° C.

The N-alkylation or benzylation of the compound of Formula XVI to give acompound of Formula XVII is carried out with a suitable alkylating orbenzylating agent, L-R₄ where L is any leaving group, known in the art,preferably selected from halogen, O-mestyl and O-tosyl group.

The N-alkylation or benzylation of the compound of Formula XVI to give acompound of Formula XVII is carried out in a suitable organic solventsuch as N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran andacetonitrile, at a temperature ranging from about 10°-100° C.

The reduction of the compound of Formula XVII to give a compound ofFormula XVIII is carried out with triphenylphosphine in the presence ofa suitable organic solvent such as tetrahydrofuran and water.

The compound XVIII on treatment with acid chlorides in a suitablesolvent selected from the group consisting of dichloromethane,dichloroethane and chloroform gives the compound of Formula IV.

The acid chlorides may be selected from the group consisting ofphenylacetylchloride, 4-nitrophenyl sulfonyl chloride, benzene sulfonylchloride, benzyloxyacetyl chloride, 4-methoxy phenylsulfonyl chlorideand 4-bromophenylsulfonyl chloride.

Suitable salts of the compounds represented by the Formula IV wereprepared so as to solubilize the compound in aqueous medium forbiological evaluations. Examples of such salts include pharmacologicallyacceptable salts such as inorganic acid salts (e.g. hydrochloride,hydrobromide, sulphate, nitrate and phosphorate), organic acidsalts(e.g. acetate, tartrate, citrate, fumarate, maleate,toluenesulphonate and methanesulphonate). When carboxyl group isincluded in the Formula I as a substituent, it may be an alkali metalsalt (e.g. sodium, potassium, calcium, magnesium, and the like). Thesesalts may be prepared by the usual prior art techniques, such astreating the compound with an equivalent amount of inorganic or organic,acid or base in a suitable solvent.

In the above schemes, where specific bases, condensing agents,protecting groups, deprotecting agents, N-alkylating benzylating agents,solvents etc. mentioned, it is to be understood that other bases,condensing agents, protecting groups, deprotecting agents, N-alkylating,benzylating agents, solvents etc. known to those skilled in the art maybe used. Similarly, the reaction temperature and duration may beadjusted according to the desired needs.

Preferred compounds according to the invention and capable of beingproduced by Scheme I-IV and are shown in Table 1 include:

Compound No. Chemical Name 1A.(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide 1B.(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide 2.(2R(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S, 3R or 3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide3. (2Ror 2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenyl acetamide 4. (2R or2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S, 3R or3S)-3-fluorocyclopentyl]-2-hydroxy- 2-phenyl acetamide 5.(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S, 3R or 3S)-3-phenyl acetylamino cyclopentyl]-2-hydroxy-2-phenylacetamide 6.(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S, 3R or 3S)-3-(4-nitrophenyl)sulphonylaminocyclopentyl]-2- hydroxy-2-phenylacetamide 7.(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S, 3R or 3S)-3-phenylsulphonylamino cyclopentyl]-2-hydroxy-2-phenylacetamide 8.(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S, 3R or 3S)-3-benzyloxyacetylamino cyclopentyl]-2-hydroxy-2-phenylacetamide 9.(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S, 3R or 3S)-3-(4-methoxyphenyl) sulphonylaminocyclopentyl]-2-hydroxy-2-phenylacetamide 10. (2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S, 3R or 3S)-3-(4-bromophenyl)sulphonylaminocyclopentyl]- 2-hydroxy-2-phenylacetamide

Table I Formula-IV

S.No. R₁₁ R₁₂ Z Q R₄  1A F F NH CH₂ CH₂Ph  1B F F NH CH₂ CH₂Ph  2 H F NHCH₂ CH₂Ph  3 F F NH CH₂ CH₂Ph  4 H F NH CH₂ CH₂Ph  5 H

NH CH₂ CH₂Ph  6 H

NH CH₂ CH₂Ph  7 H

NH CH₂ CH₂Ph  8 H

NH CH₂ CH₂Ph  9 H

NH CH₂ CH₂Ph 10 H

NH CH₂ CH₂Ph (Formula I, W is (CH₂)p where p = 0, X is no atom, Y is(CH₂)q where q = 0, R₆ = R₇ = H, R₂ =

, s = 1, R₁ = OH, Ar = phenyl)

Because of their valuable pharmacological properties, the compounds ofthe present invention may be adminisered to an animal for treatmentorally, or by parenteral route. The pharmaceutical compositions of thepresent invention are preferably produced and administered in dosageunits, each unit containing a certain amount of at least one compound ofthe invention and/or at least one physiologically acceptable additionsalt thereof. The dosage may be varied over extremely wide limits as thecompounds are effective at low dosage levels and relatively free oftoxicity. The compounds may be administered in the low micromolarconcentration, which is therapeutically effective, and the dosage may beincreased as desired up to the maximum dosage tolerated by the patient.

The present invention also includes within its scope prodrugs of thecompounds of Formula I, II, III and IV. In general, such prodrugs willbe functional derivatives of these compounds, which readily areconverted in vivo into the defined compounds. Conventional proceduresfor the selection and preparation of suitable prodrugs are known.

The present invention also includes the enantiomers, diastereomers,N-oxides, polymorphs, solvates and pharmaceutically acceptable salts ofthese compounds as well as metabolites having the same type of activity.The present invention further includes the pharmaceutical compositioncomprising the molecules of Formulae I, II, III and IV or prodrugs,metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvatesor pharmaceutically acceptable salts thereof, in combination withpharmaceutically acceptable carrier and optionally included excipient.

The examples mentioned below demonstrate the general synthetic procedureas well as the specific preparation of the preferred compound. Theexamples are provided to illustrate the details of the invention andshould not be constrained to limit the scope of the present invention.

EXPERIMENTAL DETAILS

Various solvents, such as acetone, methanol, pyridine, ether,tetrahydrofuran, hexane, and dichloromethane, were dried using variousdrying agents according to the procedure described in the literature. IRspectrum were recorded as nujol mulls or a thin neat film on a PerkinElmer Paragon Instrument and Nuclear Magnetic Resonance (NMR) wererecorded on a Varian XL-300 MHz instrument using tetramethylsilane as aninternal standard.

EXAMPLE 1 Preparation of(2R)-(1α,5α,6α)-N-3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (CompoundNos. 1A and 1B) Step a: Preparation of(2R,5R)-2-tert-butyl-5-phenyl-1,3-dioxalan-4-one

The compound was synthesized following the procedure described in J.Org. Chem. 2000; 65:6283.

Step b: Preparation of (2R,5R)-2-tert-butyl-5-[(1R or1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxalan-4-one

To a suspension of the compound obtained at step a (1.36 mmol) intetrahydrofuran (12 ml) was added lithium diisopropyl amide (LDA) intetrahydrofuran (1.5 mmol) drop wise at −78° C. under nitrogenatmosphere. The reaction mixture was stirred at the same temperature for2 hours. A solution of 2-cyclopenten-1-one (1.52 mmol) intetrahydrofuran (2 ml) was added to the reaction mixture dropwise andstirred for additional 3 hours. The reaction mixture was quenched withsaturated aqueous ammonium chloride solution and extracted with ethylacetate. The organic layer was dried and the residue obtained afterremoving the solvents in vacuo was purified by column chromatography(100-200 mesh silica gel). The product was eluted with 10%ethylacetate-hexane mixture.

¹HNMR(CDCl₃) δ-values: 7.70-7.26 (m,5 Ar—H), 5.43-5.37 (d, 1H),2.91-2.88 (m,1H), 2.37-1.77 (m, 6H), 0.92 (s, 9H) IR(DCM): 1791 and 1746cm⁻¹

Step c: Preparation of (2R,5R)-2-tert-butyl-5-[(1R or1S)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxalan-4-one

To a solution of the compound of step-b (1 mmol) in chloroform (15 ml)was added diethyl amino sulphur trifluoride (DAST), (3.3 mmol) at 0° C.under nitrogen atmosphere. The reaction mixture was stirred at the sametemperature for 30 minutes and then at room temperature for 3 days.After being cooled to 0° C., the reaction mixture (RM) was quenchedcarefully by adding water. The organic layer was separated and theaqueous layer extracted with chloroform. The combined organic layerswere dried and the residue obtained after removing the solvent waspurified by column chromatography (100-200 mesh size silica gel) elutingthe compound with 5% ethylacetate-hexane mixture.

¹HNMR(CDCl₃) δ-values: 7.73-7.35 (m, 5 Ar—H), 5.49 (s, 1H), 2.86-2.82(m, 1H), 2.27-1.80 (m, 6H), 0.98 (s,H) IR(DCM): 1793 cm⁻¹

Step d: Preparation of (2R) [(1S or 1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylaceticacid

The solution of the compound of step-c (1 mmol) in methanol (10 ml) wasstirred with 3N aqueous sodium hydroxide solution for overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure. The residue was diluted with water and extracted withdichloromethane. The aqueous layer was acidified with conc. hydrochloricacid and extracted with ethylacetate. The organic layer was dried andconcentrated under reduced pressure to give the product.

m.pt.:123° C. ¹HNMR(CDCl₃) δ-values: 7.69-7.37(m, 5 Ar—H), 3.29-3.20(m,1H), 2.39-1.68 (m, 6H)

Step e: Preparation of(1α,5α,6α)-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane

The compound was synthesized as per the procedure of EP0413455A2.

Step f: Preparation of(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide

A solution of (2R)-[(1S or1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid (1 mmol) and(1α,5α,6α)-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane(1.1 mmol) inDMF (10 ml) was cooled to 0° C. 1-Hydroxybenzotriazole (HOBT, 1.1 mmol)and N-methylmorpholine (NMM, 2 mmol) were added to the reaction mixtureand reaction mixture stirred for 1 hour at 0° C.1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDC.HCl) (1 mmol) wasadded to the reaction mixture at 0° C. The reaction mixture was stirredat 0° C. for 1 hour 30 minutes and then at room temperature forovernight. The reaction mixture was poured into saturated sodiumbicarbonate solution and extracted with ethylacetate. The organic layerwas washed with water and dried. The residue obtained after the removalof solvent was purified by column chromatography (100-200 mesh silicagel) eluting the compounds with 25-30% ethylacetate-hexane mixture.

Compound-1A:

¹HNMR (CDCl₃) δ-values: 7.58-7.22 (m, 10 ArH), 6.33 (bs, 1H), 3.56 (s,2H), 3.30 (m, 1H), 3.05-2.89 (m, 4H), 2.32-2.29 (m, 2H), 2.16-1.21 (m,9H) IR (KBr): 1654 cm⁻¹

Compound-1B:

¹HNMR (CDCl₃) δ-values: 7.58-7.22 (m, 10 ArH), 6.39 (bs, 1H), 3.56 (s,2H), 3.48 (m, 1H), 3.48 (m, 1H), 3.07-2.89 (m, 4H), 2.32-2.29 (m, 2H),2.16-1.21 (m, 9H) IR (KBr): 1652 cm⁻¹

Compound 1A and Compound 1 B are a Pair of Diastereomers.

EXAMPLE 2 Preparation of(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenyl acetamide(Compound No. 2) Step-a: Preparation of (2R)-2-tert-butyl-5-[(1R or 1S,3R or 3S)-3-hydroxy cyclopentyl]-5-phenyl-1,3-dioxalan-4-one

To a solution of (2R,5R)-2-tert-butyl-5-[(1R or1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxalan-4-one (1 mmol) in methanol(10 ml) cooled to 0° C., sodium borohydride (2 mmol) was added in smalllots with stirring. The reaction mixture was stirred at 0° C. for 1 hr.It was concentrated under reduced pressure and the residue diluted withwater and extracted with ethylacetate. The organic layer was dried andthe residue obtained after the removal of solvents was purified bycolumn chromatography (100-200 mesh silica gel) eluting the compoundwith 20% ethylacetate-hexane mixture.

¹HNMR(CDCl₃) δ-values: 7.68-7.29 (m, 5H, ArH), 5.45 (d, 1H), 4.30 (m,1H), 3.25 (m, 1H), 2.65-2.63 (m, 1H), 1.80-1.63 (m, 6H), 0.92 (s, 9H)IR(DCM): 1789 cm⁻¹, 3386 cm⁻¹

Step-b: Preparation of (2R)-2-tert-butyl-5-[1R or 1S, 3R or35]-3-fluorocyclopentyl]-5-phenyl-1,3-dioxolan-4-one

The solution of the compound of step-a (1 mmol) in chloroform (10 ml)was cooled to 0° C. and DAST (1.5 mmol) was added dropwise undernitrogen atmosphere. The reaction mixture (RM) was stirred at 0° C. for30 minutes and then at room temperature for 3 days. The RM was cooledand carefully quenched with aqueous ammonium chloride solution. Theorganic layer was separated and aqueous layer extracted withethylacetate. The combined organic layer was dried and residue obtainedafter removing the solvents was purified by column chromatography(100-200 mesh, silica gel) eluting the compound with 5%ethylacetate-hexane mixture.

¹HNMR(CDCl₃) δ-values: 7.68-7.28 (m, 5H, Ar—H), 5.46 (d, 1H), 5.39 (m,1H), 2.90 (m, 1H), 1.98-1.25 (m, 6H), 0.93 (s, 9H)

Step-c: Preparation of (2R)-[(1R or 1S, 3R or3S]-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The compound was synthesized following the procedure of Example 1,step-d using (2R,5R)-2-tert-butyl-5-[(1R or 1S, 3R or3S)-3-fluorocyclopentyl]-5-phenyl-1,3-dioxolan-4-one instead of(2R,5R)-2-tert-butyl-5-[(1R or1S)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxolan-4-one.

¹HNMR(CDCl₃) δ-values: 7.66-7.27 (m, 5 Ar—H), 5.30-5.00 (m, H),3.32-3.16 (m, 1H), 2.05-1.26 (m, 6H). IR(DCM): 1710 cm⁻¹

Step-d: Preparation of(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[1Ror 1S, 3R or 3S]-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide

The compound was synthesized following the procedure of Example 1,step-f, using (2R)-[(1R or 1S, 3R or3S-3-fluorocyclopentyl]-2-hydroxy-2-phenyl acetic acid instead of(2R)-[(1R or 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid.

¹HNMR(CDCl₃) δ-values: 7.71-7.24 (m, 10H, Ar—H), 6.04 (b, 1H), 5.21-5.10(m, 1H), 3.55 (s, 2H), 3.26-2.86 (m, 5H), 2.31-2.28 (m, 2H), 2.00-1.20(m, 9).

EXAMPLE 3 Preparation of (2R or2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenyl acetamide (CompoundNo. 3) Step a: Preparation of (2R or 2S,5R or5S)-2-tert-butyl-5-phenyl-1,3-dioxalan-4-one

The compound was synthesized as per the procedure described in J. Org.Chem. 2000; 65:6283, using DL-Mandelic acid instead of R-(−)-Mandelicacid.

Step b: Preparation of (2R or 2S,5R or 5S)-2-tert-butyl-5-[(1R or1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxalan-4-one

The compound was synthesized following the procedure of Example 1,step-b, using (2R or 2S, 5R or5S)-2-tert-butyl-5-phenyl-1,3-dioxalan-4-one instead of(2R,5R)-2-tert-butyl-5-phenyl-1,3-dioxalan-4-one.

Step c: Preparation of (2R or 2S, 5R or 5S)-2-tert-butyl-5-[(1R or1S)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxalan-4-one

The compound was prepared following the procedure of Example 1, step-c,using (2R or 2S, 5R or 5S)-2-tert-butyl-5-[(1R or1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxalan-4-one instead of(2R,5R)-2-tert-butyl-5-[(1R or1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxalan-4-one.

¹HNMR(CDCl₃) δ-values: 7.67-7.29(m, 5 Ar—H), 5.34(s, 1H), 2.80-2.76(m,1H), 2.23-1.70(m, 6H), 0.92(s, 9H)

Step d: Preparation of (2R or 2S,5R or 5S)-2-[(1R or1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid

The compound was synthesized following the procedure of Example 1,step-d-d, using (2R or 2S, 5R or 5S)-2-tert-butyl-5-[(1R or1S)-3,3-difluorocyclopentyi]-5-phenyl-1,3-dioxalan-4-one instead of(2R,5R)-2-tert-butyl-5-[(1R or1S)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxalan-4-one.

¹HNMR(CDCl₃) δ-values: 7.65-7.31 (m, 5 Ar—H), 3.23-3.14(m, 1H),2.25-1.62(m 6H) IR (KBr): 1724 cm⁻¹

Step e: Preparation of (2R or2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyly)-yl]-2-[(1Ror 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenyl acetamide

The compound was synthesized following the procedure of Example 1,step-f, using (2R or 2S, 5R or 5S)-2-[(1R or1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid instead of(2R,5R)-2-[(1R or 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylaceticacid.

¹HNMR(CDCl₃) δ-values: 7.58-7.23 (m, 10 Ar—H), 6.33 (bs, 1H), 3.56 (s,2H), 3.47 (s, 1H), 3.33-3.25(m, 1H), 3.05-2.88(m, 4H), 2.31-2.28(m, 2H),2.21-1.66(m, 9H) IR (KBr): 1652 cm⁻¹

HPLC: Single compound (Diastereomers could not be separated).

EXAMPLE 4 Preparation of (2R or2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenyl acetamide(Compound No. 4) Step a: Preparation of (2R or 2S, 5R or5S)-2-tert-butyl-5-[(1R or 1S, 3R or3)-3-hydroxycyclopentyl]-5-phenyl-1,3-dioxalan-4-one

To a solution of (2R or 2S, 5R or 5S)-2-tert-butyl-5-[(1R or1S)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one (1 mmol) in methanol(10 ml)cooled to 0° C. Sodium borohydride (2 mmol) was added in smalllots with stirring. The RM was stirred at 0° C. for 1 hour. It wasconcentrated under reduced pressure and the residue diluted with waterand extracted with EtOAc. The organic layer was dried and the residueobtained after removal of solvents was purified by column chromatography(100-200 mesh silicagel) eluting the compound with 20% EtOAc-hexanemixture.

¹HNMR(CDCl₃) δ-values: 7.68-7.29(m, 5 Ar—H), 5.45(d, 1H), 4.3(m, 1H),−3.25(m, 1H), 2.65-2.63(m, 1H), 1.80-1.63(m, 6H), 0.92(s, 9H) IR (DCM):1789 cm⁻¹, 3386 cm⁻¹

Step b: Preparation of (2R or 2S, 5R or 5S)-2-tert-butyl-5-[(1R or 1S,3R or 3S)-3-fluorocyclopentyl]-5-phenyl-1,3-dioxalan-4-one

A solution of the compound of step-a (1 mmol) in chloroform (10 ml) wascooled to 0° C. and DAST (1.5 mmol) was added dropwise under nitrogenatmosphere. The RM was stirred at 0° C. for 30 minutes and then at roomtemperature for 3 days. The RM was cooled and quenched with aqueousammonium chloride solution. The organic layer was separated and aqueouslayer extracted with EtOAc. The combined organic layers were dried andthe residue obtained after removing the solvents was purified by columnchromatography (100-200 mesh size, silica gel) eluting the compound with5% EtOAc-hexane mixture.

¹HNMR(CDCl₃) δ-values: 7.69-7.23(m, 5 Ar—H), 5.42(d, 1H), 5.28-5.16(m,1H), 2.92-2.86(m, 1H), 1.97-1.24(m, 6H), 0.90(s, 9H) IR (DCM): 1791 cm⁻¹

Step c: Preparation of (2R or 2S)-[(1R or 1S, 3R or3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenyl acetic acid

The compound was synthesized following the procedure of Example 1,step-d, using (2R or 2S, 5R or 5S)-2-tert-butyl-5-[(1R or 1S, 3R or3S)-3-fluorocyclopentyl]-5-phenyl-1,3-dioxalan-4-one instead of(2R,5R)-2-tert-butyl-5-[(1R or1S)-3,3-difluorocyclopentyl]-5-phenyl-1,3-dioxalan-4-one

¹HNMR(CDCl₃) δ-values: 7.66-7.25(m, 5 Ar—H), 5.304.99(m, 1H),3.81-3.76(m, 1H), 2.01-1.64(m, 6H) IR (KBr): 1722 cm⁻¹

Step d: Preparation of (2R or2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenyl acetamide

The compound was synthesized following the procedure of Example 1,step-f, using (2R or 2S)-[(1R or 1S, 3R or3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenyl acetic acid instead of(2R)-[(1R or 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetic acid.

¹HNMR(CDCl₃) δ-values: 7.66-7.25(m, 10 Ar—H),6.05(bs, 1H), 5.30-5.03 (m,1H),3.98 (s, 2H), 3.56-2.87 (m, 5H), 2.31-2.28(m, 2H),1.97-1.11(m, 9H)IR (DCM): 1652 cm⁻¹

EXAMPLE 5 Preparation of(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-phenylacetylaminocyclopentyl]-2-hydroxy-2-phenylacetamide (Compound No. 5) Step a:Preparation of (2R,5R)-2-tert-butyl-5-[(1R or 1S, 3R or3S)-3-azidocyclopentyl]-5-phenyl-1,3-dioxalan-4-one

To a solution of (2R,5R)-2-tert-butyl-5-[(1R or 1S, 3R or3S)-3-hydroxycyclopentyl]-5-phenyl-1,3-dioxalan-4-one (1 mmol) andtriethylamine (2.5 mmol) in ethyl acetate (10 ml) was added methanesulphonyl chloride (2 mmol) and the RM stirred for 1 hour at 0° C. andthen at room temperature for 1 hour. Saturated aq. sodium bicarbonatesolution was added, the organic layer separated and washed with waterThe organic layer was dried and the residue obtained after the removalof solvent was used as such for the next step.

The residue (1 mmol) was dissolved in DMF (10 ml) and to it sodium azide(4 mmol) was added. The RM was heated at 90-95° C. for 4 hours, cooledto room temperature, diluted with water and extracted with EtOAc. Theorganic layer was dried and the residue obtained after removing thesolvent was used as such.

¹HNMR(CDCl₃) δ-values: 7.66-7.26 (m, 5 Ar—H), 5.40 (s, 1H), 4.00-3.97(m, 1H), 2.83-2.78 (m, 1H), 1.80-1.04 (m, 6H), 0.93 (s, 9H) IR (DCM):1791 and 2099 cm⁻¹

Step b: Preparation of (2R)-[(1R or 1S, 3R or3S)-3-azidocyclopentyl]-2-hydroxy-2-phenyl acetic acid

To a solution of the compound of step-a (1 mmol) in 10 ml of methanol,3N aq. sodium hydroxide solution was added and the RM stirred forovernight at room temperature. The RM was concentrated under reducedpressure, diluted with water and extracted with dichloromethane. Theaqueous layer was acidified with 1N hydrochloric acid and extracted withchloroform. The organic layer was washed with water, dried andconcentrated under reduced pressure to give the required product.

¹HNMR(CDCl₃) δ-values: 7.65-7.26(m, 5 Ar—H), 4.07-3.97 (m, 1H),3.22-3.14 (m, 1H), 1.89-1.25 (m, 6H) IR (DCM): 1712 and 2102 cm⁻¹

Step c: Preparation of(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-azidocyclopentyl]-2-hydroxy-2-phenylacetamide

To a solution of the compound of step-b (1 mmol) and(1α,5α,6α)-6-aminomethyl-3-benzyl-3-azabicyclo[3.1.0]hexane (0.9 mmol)in DMF (10 ml) was added NMM (2 mmol) and HOBT (1.1 mmol) at 0° C. andstirred at the same temperature for 1 hour. EDC.HCl (1 mmol) was thenadded and the RM stirred for 1 hour at 0° C. and then at roomtemperature for 4 days. The RM was poured into water and extracted withEtOAc. The organic layer was dried and the residue obtained after theremoval of solvent was purified by column chromatography.

¹HNMR(CDCl₃) δ-values: 7.74-7.22 (m, 10 Ar—H), 6.07 (bs, 1H), 3.98-3.96(m, 1), 3.55 (s, 2H), 3.04-2.99 (m, 5H), 2.31-2.28 (m, 2H), 1.76-1.19(m, 9H) IR (DCM): 1654 and 2097 cm⁻¹

Step-d: Preparation of(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-aminocyclopentyl]-2-hydroxy-2-phenyl acetamide

To a solution of the compound of, step-c, (9 mmol) in a mixture of THFand water (75+15 ml), triphenyl phosphine (27 mmol) was added and the RMrefluxed for 18 hours. The RM was cooled to room temperature, solventremoved in vacuo and the residue diluted with water. The pH was madeacidic with 1N HCl and the RM extracted with chloroform. The aqueouslayer was then made basic with 1N sodium hydroxide solution andextracted with chloroform. The organic layer was washed with water,dried and concentrated under reduced pressure. The residue was used assuch for the next step.

Step e: Preparation of(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)₃-phenylacetylaminocydopentyl]-2-hydroxy-2-phenylacetamide

To a solution of the compound of step-d, triethylamine (2.2 mmol),dimethyl aminopyridine (1 mg) in chloroform was added phenylacetylchloride (2.2 mmol) at 0° C. The RM was stirred for overnight at roomtemperature. Aqueous sodium hydroxide was added and the organic layerseparated. The organic layer was washed with water, dried and thesolvent removed in vacuo. The residue was purified by columnchromatography.

m.pt.:56-61° C. IR (DCM): 1650 cm⁻¹

EXAMPLE 6 Preparation of(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or3S)-34(4-nitrophenyl)sulphonylamino-cyclopentyl]-2-hydroxy-2-phenylacetamide(Compound No. 6)

The compound was synthesized following the procedure of Example 5,step-e, using 4-nitrophenyl sulphonyl chloride instead of phenylacetylchloride.

m.pt.:67-71° C. ¹HNMR(CDCl₃) δ-values: 8.35-8.26 (m, 2 ArH), 8.06-7.97(m, 2 ArH), 7.51-7.26 (m, 10 ArH), 6.34 (bs, 1H), 3.67-2.90 (m, 9H),2.35-1.15 (m, 10H) IR (KBr): 1652 and 1529 cm⁻¹

EXAMPLE 7 Preparation of(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or3S)-3-phenylsulphonylaminocyclopentyl]-2-hydroxy-2-phenylacetamide(Compound No. 7)

The compound was synthesized following the procedure of Example 5,step-e, using benzene sulphonyl chloride instead of phenylacetylchloride.

m.pt.:52-56° C. ¹HNMR(CDCl₃) δ-values: 7.88-7.26 (m, 15 ArH), 6.26 (bs,1H), 3.67-2.86(m, 9H), 2.35-1.10(m, 12H) IR (KBr): 1654 cm⁻¹

EXAMPLE 8 Preparation of(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2[(1Ror 1S, 3R or3S)-3-benzyloxyacetylaminocyclopentyl]-2-hydroxy-2-phenylacetamide(Compound No. 8)

The compound was synthesized following the procedure of Example 5,step-e, using benzyloxyacetyl chloride instead of phenylacetyl chloride.

¹HNMR(CDCl₃) δ-values: 7.59-7.26 (m, 15 ArH), 6.26 (bs, 1H), 4.55 (d,2H), 3.95-3.56 (m, 4H), 3.28 (s, 2H), 3.04-2.90 (m, 4H), 2.32-2.29 (m,2H), 2.05-1.13 (m, 10H) IR (DCM): 1655 cm⁻¹

EXAMPLE 9 Preparation of(2R)-(1α,α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-(4-methoxyphenyl)sulphonylamino cyclopentyl]-2-hydroxy-2-phenylacetamide (Compound No. 9)

The compound was synthesized following the procedure of Example 5,step-e, using 4-methoxyphenyl sulphonyl chloride instead of phenylacetylchloride.

¹HNMR(CDCl₃) δ-values: 7.85-6.96(m, 14 ArH), 6.30(bs, 1H),3.89(s, 3H),3.6 (s, 2H), 3.05-2.91 (m, 5H), 2.36-2.34 (m, 2H), 1.83-0.93 (m, 10H) IR(DCM): 1661 cm⁻¹

EXAMPLE 10 Preparation of(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or3S)-3-(4-bromophenyl)sulphonylaminocyclopentyl]-2-hydroxy-2-phenylacetamide(Compound No. 10)

The compound was synthesized following the procedure of Example 5,step-e, using 4-bromophenyl sulphonyl chloride instead of phenylacetylchloride.

¹HNMR(CDCl₃) δ-values: 7.73-7.26 (m, 14 ArH), 6.26 (bs, 1H), 3.57-2.86(m, 7H), 2.33-2.29(m, 2H), 1.85-1.19(m, 10H) IR (DCM): 1651 cm⁻¹

BIOLOGICAL ACTIVITY

Radioligand Binding Assays:

The affinity of test compounds for M₂ and M₃ muscarinic receptorsubtypes was determined by [³H]-N-methylscopolamine binding studiesusing rat heart and submandibular gland respectively as described byMoriya et al., (Life Sci, 1999, 64(25):2351-2358) with minormodifications.

Membrane preparation: Submandibular glands and heart were isolated andplaced in ice cold homogenising buffer (HEPES 20 mM, 10 mM EDTA, pH 7.4)immediately after sacrifice. The tissues were homogenised in 10 volumesof homogenising buffer and the homogenate was filtered through twolayers of wet gauze and filtrate was centrifuged at 500 g for 10 min.The supernatant was subsequently centrifuged at 40,000 g for 20 min. Thepellet thus obtained was resuspended in same volume of assay buffer(HEPES 20 mM, EDTA 5 mM, pH 7.4) and were stored at −70° C. until thetime of assay.

Ligand binding assay: The compounds were dissolved and diluted in DMSO.The membrane homogenates (150-250 μg protein) were incubated in 250 μlof assay buffer (HEPES 20 mM, pH 7.4) at 24-25° C. for 3 h. Non-specificbinding was determined in the presence of 1 μM atropine. The incubationwas terminated by vacuum filtration over GF/B fiber filters(Wallac). Thefilters were then washed with ice cold 50 mM Tris HCl buffer (pH 7.4).The filter mats were dried and bound radioactivity retained on filterswas counted. The IC₅₀ & Kd were estimated by using the non-linear curvefitting program using G Pad Prism software. The value of inhibitionconstant Ki was calculated from competitive binding studies by usingCheng & Prusoff equation (Biochem Pharmacol, 1973, 22: 3099-3108),Ki=IC₅₀/(1+L/Kd), where L is the concentration of

[³H]NMS used in the particular experiment.

Functional Experiments Using Isolated Rat Bladder:

Methodology:

Animals were euthanized by overdose of urethane and whole bladder wasisolated and removed rapidly and placed in ice cold Tyrode buffer withthe following composition (mMol/L) NaCl 137; KCl 2.7; CaCl₂ 1.8; MgCl₂0.1; NaHCO₃ 11.9; NaH₂PO₄ 0.4; Glucose 5.55 and continuously gassed with95% O₂ and 5% CO₂.

The bladder was cut into longitudinal strips (3 mm wide and 5-6 mm long)and mounted in 10 ml organ baths at 30° C., with one end connected tothe base of the tissue holder and the other end connected to a polygraphthrough a force displacement transducer. Each tissue was maintained at aconstant basal tension of 2 g and allowed to equilibrate for 1 hourduring which the PSS was changed every 15 min. At the end ofequilibration period the stabilization of the tissue contractileresponse was assessed with 1 μmol/L of Carbachol consecutively for 2-3times. Subsequently a cumulative concentration response curve tocarbachol (10⁻⁹ mol/L to 3×10⁻⁵ mol/L) was obtained. After severalwashes, once the baseline was achieved, cumulative concentrationresponse curve was obtained in presence of NCE (NCE added 20 min. priorto the second CRC).

The contractile results were expressed as % of control E max. ED50values were calculated by fitting a non-linear regression curve (GraphPad Prism). pKB values were calculated by the formula pKB=−log [(molarconcentration of antagonist/(dose ratio-1))]

where,

-   dose ratio=ED50 in the presence of antagonist/ED50 in the absence of    antagonist.

The result of the in-vitro test are listed in Table II.

In-Vitro Tests

TABLE II Receptor Binding Assay M₂ M₃ Functional pKi pKi Assay pK_(B)Compound No. 1A 6.87 8.25 9.1 ± 0.2 Compound No. 1B 6.64 8.21 8.98 ±0.06 Compound No. 2 6.9 8.4 8.84 ± 0.07 Compound No. 3 6.6 8.2 8.55 ±0.25 Compound No. 4 6.86 8.23 8.33 ± 0.15 Compound No. 5 6.08 7.4 7.07 ±0.11 Compound No. 6 <5.8 7.66 7.21 ± 0.20 Compound No. 7 <5.8 7.3 6.89 ±0.29 Compound No. 8 6.68 7.46 7.08 ± 0.18 Compound No. 9 <6 6.69 —Compound No. 10 <6 6.89 —

While the present invention has been described in terms of its specificembodiments, certain modifications and equivalents will be apparent tothose skilled in the art and are intended to be included within thescope of the present invention.

1. A compound having the structure of Formula I

and its pharmaceutically acceptable salts, pharmaceutically acceptableenantiomers, diastereomers, N-oxides, wherein Ar represents an aryl ringwhich may be unsubstituted or substituted by one to three substituentsindependently selected from lower alkyl (C₁-C₄), lower perhalo alkyl(C₁-C₄), cyano, hydroxy, nitro, lower alkoxy (C₁-C₄), lower perhaloalkoxy (C₁-C₄), unsubstituted amino, N-lower alkyl (C₁-C₄) amino orN-lower alkyl (C₁-C₄) amino carbonyl; R₁ represents a hydrogen, hydroxy,hydroxymethyl, amino, alkoxy, carbamoyl or halogen (fluorine, chlorine,bromine or iodine); R₂ represents a C₃-C₇ cycloalkyl ring in which from1 to 4 hydrogen atoms are substituted with fluorine atoms, amides orsulphonamide derivatives; W represents (CH₂)_(p), where p represents 0or 1; X represents no atom; Y represents (CH₂)_(q) wherein q represents0; Z represents oxygen, sulphur or NR₁₀, wherein R₁₀ represents hydrogenor C₁₋₆ alkyl; Q represents (CH₂)_(n) wherein n represents 1 to 4, orCHR₈ wherein R₈ represents H, OH, C₁₋₆, alkyl, alkenyl, alkoxy, orCH₂CHR₉ wherein R₉ represents H, OH, lower alkyl (C₁-C₄) or lower alkoxy(C₁-C₄); R₆ and R₇ are independently selected from H, CH₃, COOH, CONH₂,NH₂ or CH₂NH₂; and R₄ represents a C₁-C₁₅ saturated or unsaturatedaliphatic hydrocarbon group in which from 1 to 6 hydrogen atoms may besubstituted with the group independently selected from halogen,arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to2 hetero atoms selected from the group consisting of nitrogen, oxygenand sulphur atoms with an option that any 1 to 3 hydrogen atoms on thering in said arylalkyl, arylalkenyl, hetero arylalkenyl group may besubstituted with lower alkyl (C₁-C₄), lower perhalo alkyl (C₁-C₄),cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy(C₁-C₄), lower perhaloalkoxy (C₁-C₄), unsubstituted amino, N-loweralkylamino (C₁-C₄) or N-lower alkylamino carbonyl (C₁-C₄).
 2. Thecompound of claim 1, wherein the compound has the structure of FormulaII,

wherein Ar represents an aryl which may be unsubstituted or substitutedby one to three substituents independently selected from lower alkyl(C₁-C₄), lower perhalo alkyl (C₁-C₄), cyano, hydroxy, nitro, loweralkoxy (C₁-C₄), lower perhalo alkoxy (C₁-C₄), unsubstituted amino,N-lower alkyl (C₁-C₄) amino or N-lower alkyl (C₁-C₄) amino carbonyl; R₁represents a hydrogen, hydroxy, hydroxymethyl, amino, alkoxy, carbamoylor halogen (fluorine, chlorine, bromine or iodine); R₂ represents aC₃-C₇ cycloalkyl ring in which from 1 to 4 hydrogen atoms aresubstituted with fluorine atoms, amides or sulphonamide derivatives; Wrepresents (CH₂)_(p), where p represents 0 or 1; X represents no atom; Yrepresents (CH₂)_(q) wherein q represents 0; Z represents oxygen,sulphur or NR₁₀, wherein R₁₀ represents hydrogen or C₁₋₆ alkyl; Qrepresents (CH₂)_(n) wherein n represents 1 to 4, or CHR₈ wherein R₈represents H, OH, C₁₋₆, alkyl, alkenyl, alkoxy, or CH₂CHR₉ wherein R₉represents H, OH, lower alkyl (C₁-C₄) or lower alkoxy (C₁-C₄); and R₄represents a C₁-C₁₅ saturated or unsaturated aliphatic hydrocarbon groupin which from 1 to 6 hydrogen atoms may be substituted with the groupindependently selected from halogen, arylalkyl, arylalkenyl,heteroarylalkyl or heteroarylalkenyl having 1 to 2 hetero atoms selectedfrom the group consisting of nitrogen, oxygen and sulphur atoms with anoption that any 1 to 3 hydrogen atoms on the ring in said arylalkyl,arylalkenyl, hetero arylalkenyl group may be substituted with loweralkyl (C₁-C₄), lower perhalo alkyl (C₁-C₄), cyano, hydroxyl, nitro,lower alkoxycarbonyl, halogen, lower alkoxy (C₁-C₄), lower perhaloalkoxy(C₁-C₄), unsubstituted amino, N-lower alkylamino (C₁-C₄) or N-loweralkylamino carbonyl (C₁-C₄).
 3. The compound of claim 1, wherein thecompound has the structure of Formula III,

wherein Ar represents an aryl which may be unsubstituted or substitutedby one to three substituents independently selected from lower alkyl(C₁-C₄), lower perhalo alkyl (C₁-C₄), cyano, hydroxy, nitro, loweralkoxy (C₁-C₄), lower perhalo alkoxy (C₁-C₄), unsubstituted amino,N-lower alkyl (C₁-C₄) amino or N-lower alkyl (C₁-C₄) amino carbonyl; R₁represents a hydrogen, hydroxy, hydroxymethyl, amino, alkoxy, carbamoylor halogen (fluorine, chlorine, bromine or iodine); R₂ represents aC₃-C₇ cycloalkyl ring in which from 1 to 4 hydrogen atoms aresubstituted with fluorine atoms, amides or sulphonamide derivatives; Zrepresents oxygen, sulphur or NR₁₀, wherein R₁₀ represents hydrogen orC₁₋₆ alkyl; Q represents (CH₂)_(n) wherein n represents 1 to 4, or CHR₈wherein R₈ represents H, OH, C₁₋₆, alkyl, alkenyl, alkoxy, or CH₂CHR₉wherein R₉ represents H, OH, lower alkyl (C₁-C₄) or lower alkoxy(C₁-C₄); and R₄ represents a C₁-C₁₅ saturated or unsaturated aliphatichydrocarbon group in which from 1 to 6 hydrogen atoms may be substitutedwith the group independently selected from halogen, arylalkyl,arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphuratoms with an option that any 1 to 3 hydrogen atoms on the ring in saidarylalkyl, arylalkenyl, hetero arylalkenyl group may be substituted withlower alkyl (C₁-C₄), lower perhalo alkyl (C₁-C₄), cyano, hydroxyl,nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C₁-C₄), lowerperhaloalkoxy (C₁-C₄), unsubstituted amino, N-lower alkylamino (C₁-C₄)or N-lower alkylamino carbonyl (C₁-C₄).
 4. The compound of claim 1,wherein the compound has the structure of Formula IV,

wherein R₁₁ is hydrogen or fluoro, R₁₂ is fluoro, amide or sulphonamidederivatives and s represents 1 to 2; R₄ represents a C₁-C₁₅ saturated orunsaturated aliphatic hydrocarbon group in which from 1 to 6 hydrogenatoms may be substituted with the group independently selected fromhalogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenylhaving 1 to 2 hetero atoms selected from the group consisting ofnitrogen, oxygen and sulphur atoms with an option that any 1 to 3hydrogen atoms on the ring in said arylalkyl, arylalkenyl, heteroarylalkenyl group may be substituted with lower alkyl (C₁-C₄), lowerperhalo alkyl (C₁-C₄), cyano, hydroxyl, nitro, lower alkoxycarbonyl,halogen, lower alkoxy (C₁-C₄), lower perhaloalkoxy (C₁-C₄),unsubstituted amino, N-lower alkylamino (C₁-C₄) or N-lower alkylaminocarbonyl (C₁-C₄); Z represents oxygen, sulphur or NR₁₀, wherein R₁₀represents hydrogen or alkyl; and Q represents (CH₂)_(n) wherein nrepresents 1 to 4, or CHR₈ wherein R₈ represents H, OH, C₁₋₆, alkyl,alkenyl, alkoxy, or CH₂CHR₉ wherein R₉ represents H, OH lower alkyl(C₁-C₄) or lower alkoxy (C₁-C₄).
 5. A compound selected from the groupconsisting of:(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (CompoundNo. 1A)(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide (CompoundNo. 1B)(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide(Compound No. 2) (2R or2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide(Compound No. 3) (2R or2S)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1R or 1S, 3R or3S)-3-fluorocyclopentyl]-2-hydroxy-2-phenylacetamide (Compound No. 4)(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-phenylacetylaminocyclopentyl]-2-hydroxy-2-phenylacetamide (Compound No. 5)(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-(4-nitrophenyl)sulphonylaminocyclopentyl]-2-hydroxy-2-phenylacetamide (Compound No. 6)(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-phenylsulphonylaminocyclopentyl]-2-hydroxy-2-phenylacetamide (Compound No. 7)(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or3S)-3-benzyloxyacetylaminocyclopentyl]-2-hydroxy-2-phenylacetamide(Compound No. 8)(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-(4-methoxyphenyl) sulphonylaminocyclopentyl]-2-hydroxy-2-phenylacetamide (Compound No. 9); and(2R)-(1α,5α,6α)-N-[3-benzyl-3-azabicyclo[3.1.0]hexyl-6-(aminomethyl)-yl]-2-[(1Ror 1S, 3R or 3S)-3-(4-bromophenyl)sulphonylaminocyclopentyl]-2-hydroxy-2-phenylacetamide (Compound No. 10).
 6. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 together with pharmaceutically acceptablecarriers, excipients or diluents.
 7. A method for treatment of an animalor human suffering from a disease or disorder of the respiratory,urinary and gastrointestinal systems, wherein the disease or disorder ismediated through muscarinic receptors, and wherein the disease ordisorder is urinary incontinence, lower urinary tract symptoms (LUTS),bronchial asthma, chronic obstructive pulmonary disorders (COPD),pulmonary fibrosis, irritable bowel syndrome, obesity, diabetes andgastrointestinal hyperkinesis, the method comprising administering tosaid animal or human, a therapeutically effective amount of a compoundhaving the structure of Formula I

and its pharmaceutically acceptable salts, pharmaceutically acceptableenantiomers, diastereomers, N-oxides, wherein Ar represents an arylwhich may be unsubstituted or substituted by one to three substituentsindependently selected from lower alkyl (C₁-C₄), lower perhalo alkyl(C₁-C₄), cyano, hydroxy, nitro, lower alkoxy (C₁-C₄), lower perhaloalkoxy (C₁-C₄), unsubstituted amino, N-lower alkyl (C₁-C₄) amino orN-lower alkyl (C₁-C₄) amino carbonyl; R₁ represents a hydrogen,hydroxyhydroxymethyl, amino, alkoxy, carbamoyl or halogen (fluorine,chlorine, bromine and iodine); R₂ represents a C₃-C₇ cycloalkyl ring inwhich from 1 to 4 hydrogen atoms are substituted with fluorine atoms,amides or sulphonamide derivatives; W represents (CH₂)_(p), where prepresents 0 to 1; X represents no atom; Y represents (CH₂)_(q) whereinq represents 0; Z represents oxygen, sulphur, NR₁₀, wherein R₁₀represents hydrogen or C₁₆ alkyl; Q represents (CH₂)_(n) wherein nrepresents 1 to 4, or CHR₈ wherein R₈ represents H, OH, C₁₋₆, alkyl,alkenyl, alkoxy, or CH₂CHR₉ wherein R₉ represents H, OH, lower alkyl(C₁-C₄) or lower alkoxy (C₁-C₄); R₆ and R₇ are independently selectedfrom H, CH₃, COOH, CONH₂, NH₂ or CH₂NH₂; and R₄ represents a C₁-C₁₅saturated or unsaturated aliphatic hydrocarbon group in which from 1 to6 hydrogen atoms may be substituted with the group independentlyselected from halogen, arylalkyl, arylalkenyl, heteroarylalkyl orheteroarylalkenyl having 1 to 2 hetero atoms selected from the groupconsisting of nitrogen, oxygen and sulphur atoms with an option that any1 to 3 hydrogen atoms on the ring in said arylalkyl, arylalkenyl, heteroarylalkenyl group may be substituted with lower alkyl (C₁-C₄), lowerperhalo alkyl (C₁-C₄), cyano, hydroxyl, nitro, lower alkoxycarbonyl,halogen, lower alkoxy (C₁-C₄), lower perhaloalkoxy (C₁-C₄),unsubstituted amino, N-lower alkylamino (C₁-C₄) or N-lower alkylaminocarbonyl (C₁-C₄).
 8. The method of claim 7, wherein the compound has thestructure of Formula II,

wherein Ar represents an aryl which may be unsubstituted or substitutedby one to three substituents independently selected from lower alkyl(C₁-C₄), lower perhalo alkyl (C₁-C₄), cyano, hydroxy, nitro, loweralkoxy (C₁-C₄), lower perhalo alkoxy (C₁-C₄), unsubstituted amino,N-lower alkyl (C₁-C₄) amino or N-lower alkyl (C₁-C₄) amino carbonyl; R₁represents a hydrogen, hydroxy, hydroxymethyl, amino, alkoxy, carbamoylor halogen (fluorine, chlorine, bromine or iodine); R₂ represents aC₃-C₇ cycloalkyl ring in which from 1 to 4 hydrogen atoms aresubstituted with fluorine atoms, amides or sulphonamide derivatives; Wrepresents (CH₂)_(p), where p represents 0 or 1; X represents no atom; Yrepresents (CH₂)_(q) wherein q represents 0; Z represents oxygen,sulphur or NR₁₀, wherein R₁₀ represents hydrogen or alkyl; Q represents(CH₂)_(n) wherein n represents 1 to 4, or CHR₈ wherein R₈ represents H,OH, C₁₋₆, alkyl, alkenyl, alkoxy, or CH₂CHR₉ wherein R₉ represents H,OH, lower alkyl (C₁-C₄) or lower alkoxy (C₁-C₄; and R₄ represents aC₁-C₁₅ saturated or unsaturated aliphatic hydrocarbon group in whichfrom 1 to 6 hydrogen atoms may be substituted with the groupindependently selected from halogen, arylalkyl, arylalkenyl,heteroarylalkyl or heteroarylalkenyl having 1 to 2 hetero atoms selectedfrom the group consisting of nitrogen, oxygen and sulphur atoms with anoption that any 1 to 3 hydrogen atoms on the ring in said arylalkyl,arylalkenyl, hetero arylalkenyl group may be substituted with loweralkyl (C₁-C₄), lower perhalo alkyl (C₁-C₄), cyano, hydroxyl, nitro,lower alkoxycarbonyl, halogen, lower alkoxy (C₁-C₄), lower perhaloalkoxy(C₁-C₄), unsubstituted amino, N-lower alkylamino (C₁-C₄) or N-loweralkylamino carbonyl (C₁-C₄).
 9. The method of claim 7, wherein thecompound has the structure of Formula III,

wherein Ar represents an aryl which may be unsubstituted or substitutedby one to three substituents independently selected from lower alkyl(C₁-C₄), lower perhalo alkyl (C₁-C₄), cyano, hydroxy, nitro, loweralkoxy (C₁-C₄), lower perhalo alkoxy (C₁-C₄), unsubstituted amino,N-lower alkyl (C₁-C₄) amino or N-lower alkyl (C₁-C₄) amino carbonyl; R₁represents a hydrogen, hydroxy, hydroxymethyl, amino, alkoxy, carbamoylor halogen (fluorine, chlorine, bromine or iodine); R₂ represents aC₃-C₇ cycloalkyl ring in which from 1 to 4 hydrogen atoms aresubstituted with fluorine atoms, amides or sulphonamide derivatives; Zrepresents oxygen, sulphur or NR₁₀, wherein R₁₀ represents hydrogen orC₁₋₆ alkyl; Q represents (CH₂)_(n) wherein n represents 1 to 4, or CHR₈wherein R₈ represents H, OH, C₁₋₆, alkyl, alkenyl, alkoxy, or CH₂CHR₉wherein R₉ represents H, OH, lower alkyl (C₁-C₄) or lower alkoxy(C₁-C₄); and R₄ represents a C₁-C₁₅ saturated or unsaturated aliphatichydrocarbon group in which from 1 to 6 hydrogen atoms may be substitutedwith the group independently selected from halogen, arylalkyl,arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphuratoms with an option that any 1 to 3 hydrogen atoms on the ring in saidarylalkyl, arylalkenyl, hetero arylalkenyl group may be substituted withlower alkyl (C₁-C₄), lower perhalo alkyl (C₁-C₄), cyano, hydroxyl,nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C₁-C₄), lowerperhaloalkoxy (C₁-C₄), unsubstituted amino, N-lower alkylamino (C₁-C₄)or N-lower alkylamino carbonyl 1-C₄).
 10. The method of claim 7, whereinthe compound has the structure of Formula IV,

wherein R₁₁ is hydrogen or fluoro, R₁₂ is fluoro, amide or sulphonamidederivatives and s represents 1 to 2; R₄ represents a C₁-C₁₅ saturated orunsaturated aliphatic hydrocarbon group in which from 1 to 6 hydrogenatoms may be substituted with the group independently selected fromhalogen, arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenylhaving 1 to 2 hetero atoms selected from the group consisting ofnitrogen, oxygen and sulphur atoms with an option that any 1 to 3hydrogen atoms on the ring in said arylalkyl, arylalkenyl, heteroarylalkenyl group may be substituted with lower alkyl (C₁-C₄), lowerperhalo alkyl (C₁-C₄), cyano, hydroxyl, nitro, lower alkoxycarbonyl,halogen, lower alkoxy (C₁-C₄), lower perhaloalkoxy (C₁-C₄),unsubstituted amino, N-lower alkylamino (C₁-C₄) or N-lower alkylaminocarbonyl (C₁-C₄); Z represents oxygen, sulphur or NR₁₀, wherein R₁₀represents hydrogen or C₁₋₆ alkyl; and Q represents (CH₂)_(n) wherein nrepresents 1 to 4, or CHR₈ wherein R₈ represents H, OH, C₁₋₆, alkyl,alkenyl, alkoxy, or CH₂CHR₉ wherein R₉ represents H, OH, lower alkyl(C₁-C₄) or lower alkoxy (C₁-C₄).
 11. The method for treatment of ananimal or human suffering from a disease or disorder of the respiratory,urinary and gastrointestinal systems, wherein the disease or disorder ismediated through the muscarinic receptors, and wherein the disease ordisorder is urinary incontinence, lower urinary tract symptoms (LUTS),bronchial asthma, chronic obstructive pulmonary disorders (COPD),pulmonary fibrosis, irritable bowel syndrome, obesity, diabetes andgastrointestinal hyperkinesis, the method comprising administering tosaid animal or human a therapeutically effective amount of apharmaceutical composition of claim
 6. 12. A process of preparing acompound of Formula I

and its pharmaceutically acceptable salts, pharmaceutically acceptableenantiomers, diastereomers, N-oxides, wherein Ar represents an arylwhich may be unsubstituted or substituted by one to three substituentsindependently selected from lower alkyl (C₁-C₄), lower perhalo alkyl(C₁-C₄), cyano, hydroxy, nitro, lower alkoxy (C₁-C₄), lower perhaloalkoxy (C₁-C₄), unsubstituted amino, N-lower alkyl (C₁-C₄) amino orN-lower alkyl (C₁-C₄) amino carbonyl; R₁ represents a hydrogen, hydroxy,hydroxymethyl, amino, alkoxy, carbamoyl or halogen (fluorine, chlorine,bromine and iodine); R₂ represents a C₃-C₇ cycloalkyl ring in which from1 to 4 hydrogen atoms are substituted with fluorine atoms, amides orsulphonamide derivatives; W represents (CH₂)_(p), where p represents 0to 1; X represents no atom; Y represents (CH₂)_(q) wherein q represents0; Z represents oxygen, sulphur, NR₁₀, wherein R₁₀ represents hydrogenor C₁₋₆ alkyl; Q represents (CH₂)_(n) wherein n represents 1 to 4, orCHR₈ wherein R₈ represents H, OH, C₁₋₆, alkyl, alkenyl, alkoxy, orCH₂CHR₉ wherein R₉ represents H, OH, lower alkyl (C₁-C₄) or lower alkoxy(C₁-C₄); R₆ and R₇ are independently selected from H, CH₃, COOH, CONH₂,NH₂ or CH₂NH₂; and R₄ represents a C₁-C₁₅ saturated or unsaturatedaliphatic hydrocarbon group in which from 1 to 6 hydrogen atoms may besubstituted with the group independently selected from halogen,arylalkyl, arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to2 hetero atoms selected from the group consisting of nitrogen, oxygenand sulphur atoms with an option that any 1 to 3 hydrogen atoms on thering in said arylalkyl, arylalkenyl, hetero arylalkenyl group may besubstituted with lower alkyl (C₁-C₄), lower perhalo alkyl (C₁-C₄),cyano, hydroxyl, nitro, lower alkoxycarbonyl, halogen, lower alkoxy(C₁-C₄), lower perhaloalkoxy (C₁-C₄), unsubstituted amino, N-loweralkylamino (C₁-C₄) or N-lower alkylamino carbonyl (C₁-C₄), comprising(a) condensing a compound of Formula VI with a compound of Formula V

 wherein Ar, R₁, R₂, W, X, Y, Z, Q, R₆ and R₇ have the same meanings asdefined earlier for Formula I, to give a protected compound of FormulaVII wherein Ar, R₁, R₂, W, X, Y, Z, Q, R₆ and R₇ are the same as definedearlier and P is a protecting group for an amino group,

(b) deprotecting the compound of Formula VII in the presence of adeprotecting agent to give an unprotected intermediate of Formula VIIIwherein Ar, R₁, R₂, W, X, Y, Z, Q, R₆ and R₇ are the same as definedearlier, and

(c) N-alkylating or benzylating the intermediate of Formula VIII with asuitable alkylating agent or benzylating agent to give a compound ofFormula I.
 13. The process according to claim 12 wherein P is anyprotecting group for an amino group and is selected from the groupconsisting of benzyl or t-butyloxy carbonyl groups.
 14. The processaccording to claim 12 wherein the reaction of a compound of Formula Vwith a compound of Formula VI to give a compound of Formula VII iscarried out in the presence of a condensing agent which is selected fromthe group consisting of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride (EDC) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). 15.The process according to claim 12 wherein the reaction of a compound ofFormula V with a compound of Formula VI is carried out at about 0-140°C.
 16. The process according to claim 12 wherein the deprotection of acompound of Formula VII to give a compound of Formula VIII is carriedout with a deprotecting agent which is selected from the groupconsisting of palladium on carbon, trifluoroacetic acid (TFA) andhydrochloric acid.
 17. The process according to claim 12 wherein theN-alkylation or benzylation of a compound of Formula VIII to give acompound of Formula I is carried out with a suitable alkylating orbenzylating agent, L-R₄, wherein L is any leaving group and R₄ is thesame as defined earlier.
 18. The process according to claim 17 whereinthe leaving group is selected from the group consisting of halogen,O-mestyl and O-tosyl group.
 19. A process for preparing a compound ofFormula IV

and its pharmaceutically acceptable salts, pharmaceutically acceptableenantiomers, diastereomers, N-oxides, wherein R₁₁ is hydrogen or fluoro,R₁₂ is fluoro, amide or sulphonamide derivatives and s represents 1 to2; Z represents oxygen, sulphur, NR₁₀, wherein R₁₀ represents hydrogen,C₁₋₆ alkyl; Q represents (CH₂)_(n) wherein n represents 1 to 4, or CHR₈wherein R₈ represents H, OH, C₁₋₆, alkyl, alkenyl, alkoxy, or CH₂CHR₉wherein R₉ represents H, OH, lower alkyl (C₁-C₄) or lower alkoxy(C₁-C₄); and R₄ represents a C₁-C₁₅ saturated or unsaturated aliphatichydrocarbon group in which from 1 to 6 hydrogen atoms may be substitutedwith the group independently selected from halogen, arylalkyl,arylalkenyl, heteroarylalkyl or heteroarylalkenyl having 1 to 2 heteroatoms selected from a group consisting of nitrogen, oxygen and sulphuratoms with an option that any 1 to 3 hydrogen atoms on the ring in saidarylalkyl, arylalkenyl, hetero arylalkenyl group may be substituted withlower alkyl (C₁-C₄), lower perhalo alkyl (C₁-C₄), cyano, hydroxyl,nitro, lower alkoxycarbonyl, halogen, lower alkoxy (C₁-C₄), lowerperhaloalkoxy (C₁-C₄), unsubstituted amino, N-lower alkylamino (C₁-C₄),N-lower alkylamino carbonyl (C₁-C₄), comprising: (i) condensing acompound of Formula IX with a compound of Formula X

 where Z, Q, R₁₁, R₁₂ and s have the same meanings as defined earlierfor Formula IV, to give a protected compound of Formula XI,

(ii) deprotecting the compound of Formula XI in the presence of adeprotecting agent to give an unprotected intermediate of Formula XIIwhere Z, Q, R₁₁, R₁₂, s have the same meanings as defined earlier, and

(iii) the intermediate of Formula XII is N-alkylated or benzylated witha suitable alkylating or benzylating agent to give a compound of FormulaIV wherein Z, Q, R₁₁, R₁₂, and s are the same as defined earlier; or (b)(i) condensing a compound of Formula IX with a compound of Formula XIII

 where Z, Q, R₄ and s have the same meanings as defined earlier forFormula IV; or (c) (i) condensing a compound of Formula XIV with acompound of Formula X

 where Z, Q and s have the same meanings as defined earlier for FormulaIV, to give a protected compound of Formula XV,

(ii) deprotecting the compound of Formula XV in the presence of adeprotecting agent to give an unprotected intermediate of Formula XVI,wherein Z, Q and s have the same meanings as defined earlier,

(iii) N-alkylating or benzylating the intermediate of Formula XVI with asuitable alkylating or benzylating agent to give a compound of FormulaXVI, wherein Z, Q, R₄ and s are the same as defined earlier,

(iv) reducing the compound of Formula XVII to give a compound of FormulaXVII, wherein Z, Q, R₄ and s have the same meanings as defined earlier,and

(v) reacting a compound of Formula XVIII with acid chlorides to give acompound of Formula IV (R₁₁=H, R₁₂=substituted sulfonamide).
 20. Theprocess according to claim 19 wherein P is a protecting group for anamino group and is selected from the group consisting of benzyl ort-butoxy carbonyl groups.
 21. The process according to claim 19 whereinthe reaction of a compound of Formula IX with a compound of Formula X togive a compound of Formula XI, the reaction of a compound of FormulaXIII with a compound of Formula IX or the reaction of a compound ofFormula XIV with a compound of Formula X is carried out in the presenceof a condensing agent which is selected from the group consisting of1-(3-dimethyl aminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
 22. The process according toclaim 19 wherein the reaction of a compound of Formula IX with acompound of Formula X, the reaction of a compound of Formula XIII with acompound of Formula IX or the reaction of a compound of Formula XIV witha compound of Formula X is carried out at about 0-14° C.
 23. The processaccording to claim 19 wherein the deprotection of a compound of FormulaXI to give a compound of Formula XII or the deprotection of a compoundof Formula V to give a compound of Formula XVI is carried out with adeprotecting agent which is selected from the group consisting ofpalladium on carbon, trifluoroacetic acid (TFA) and hydrochloric acid.24. The process according to claim 19 wherein the N-alkylation orbenzylation of a compound of Formula XII to give a compound of FormulaIV or the N-alkylation or benzylation of a compound of Formula XVI togive a compound of Formula XVII is carried out with a suitablealkylating or benzylating agent, L-R₄, wherein L is any leaving groupand R₄ is the same as defined earlier.
 25. The process according toclaim 24 wherein the leaving group is selected from the group consistingof halogen, O-mestyl and O-tosyl group.
 26. The process according toclaim 19 wherein the reduction of a compound of Formula XVII to give acompound of Formula XVIII is carried out with triphenylphosphine. 27.The process according to claim 19 wherein the acid chlorides used in thereaction of a compound of Formula XVIII with acid chlorides is selectedfrom the group consisting of phenylacetyl chloride,4-nitrophenylsulfonyl chloride, benzene sulfonyl chloride,benzyloxyacetyl chloride, 4-methoxyphenylsulfonyl chloride and4-bromophenylsulfonyl chloride.